Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
  • C07D209/32—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/20—Oxygen atoms
  • C07D215/22—Oxygen atoms attached in position 2 or 4
  • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/10—Antioedematous agents; Diuretics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/08—Vasodilators for multiple indications
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
  • C07D209/32—Oxygen atoms
  • C07D209/34—Oxygen atoms in position 2
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
  • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
  • C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
  • C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• the present invention relates to new derivatives of the bicyclic aminoacids of the formula I ##STR2## in which the hydrogen atoms on the bridgehead C atoms 3a and (6+n)a have the cis or trans configuration relative to one another, wherein, in the case of the cis configuration, the carboxyl group on C atom 2 is oriented exo to the bicyclic ring system and wherein n denotes 0, 1 or 2, R 1 denotes hydrogen, (C 1 -C 6 )-alkyl which can optionally be substituted by amino, (C 1 -C 4 )-acylamino or benzoylamino, (C 2 -C 6 )-alkenyl, (C 5 -C 9 )-cycloalkyl, (C 5 -C 9 )-cycloalkenyl, (C 5 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl, aryl or partially hydrogenated aryl, which can
• Particularly suitable salts are alkali metal and alkaline earth metal salts, salts with physiologically tolerated amines and salts with inorganic or organic acids such as, for example, HCl, HBr, H 2 SO 4 , maleic acid and fumaric acid.
• aryl is to be understood as meaning phenyl or naphthyl.
• Alkyl can be straight-chain or branched.
• Compounds of the formula I have chiral C atoms in positions C-2, C-3a, C-(6+n)a, and in the C atoms labeled with an asterisk in the side chain.
• the invention relates to both the R and also the S configurations at all centers.
• the compounds of the formula I can thus be in the form of optical isomers, as diastereomers, as racemates or as mixtures thereof.
• Compounds of the formula I are preferred in which the C atom 2 in the bicyclic ring system and the C atoms labeled with an asterisk in the side chain have the S configuration.
• Preferred compounds of the formula I are those in which R 1 denotes hydrogen, (C 1 -C 3 )-alkyl, (C 2 -C 3 )-alkenyl, benzyl or 4-aminobutyl, R 2 denotes hydrogen, (C 1 -C 4 )-alkyl or benzyl and X denotes phenyl which can be mono- or di-substituted or, in the case of methoxy, tri-substituted by (C 1 -C 2 )-alkyl, (C 1 -C 2 )-alkoxy, hydroxyl, fluorine, chlorine, bromine, amino, (C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, nitro or methylenedioxy.
• the invention further relates to processes for the preparation of the compounds of the formula I.
• One variant of the process comprises reacting, by methods for amide formation known in peptide chemistry, a compound of the formula II ##STR4## wherein R 1 , R 2 , X, Y and Z have the meanings as in formula I, with a compound of the formula III ##STR5## in which the H atoms on the C atoms 3a and (6+n)a have the cis or trans configuration relative to one another, wherein, in the case of the cis configuration, the group --CO 2 W is oriented exo to the bicyclic ring system and wherein n denotes 0, 1 or 2 and W denotes a radical which can be split off by hydrogenolysis or by acid, in particular a benzyl or a tert.-butyl radical, and then splitting off the radical W by catalytic hydrogenation or acid treatment and, where appropriate, also splitting off the radical R 2 by additional acid or base treatment, the free carboxylic
• R 2 and X have the meanings as in formula I, and splitting off the radical W and, if appropriate, the radical R 2 as described above, or comprise reacting in a known manner in a Mannich reaction (Bull. Soc. Chim. France 1973, page 625) a compound of the abovementioned formula IV with a compound of the general formula VI, wherein R 2 has the meaning as in formula I, and with a compound of the general formula VII ##STR7## wherein X has the meaning as in formula I, and subsequently splitting off the radical W and, if appropriate, the radical R 2 as described above to form the free carboxyl groups.
• compounds of the formula I with Y and Z being hydrogen can also be prepared in such a manner that a compound of the abovementioned formula IV is reacted in accordance with the procedure described in J. Amer. Chem. Soc. 93 2897 (1971) with a compound of the formula VIII ##STR8## wherein R 2 and X have the meanings as in formula I, and the Schiff's bases obtained are reduced and subsequently the radical W and, if appropriate, the radical R 2 are split off as described above to form the free carboxyl groups, or that a compound of the formula I, in which Y and Z together denote oxygen, obtained according to the above procedures is reduced catalytically with hydrogen.
• the reduction of the Schiff's bases can be carried out catalytically, electrolytically or with reducing agents, such as, for example, sodium borohydride or sodium cyanoborohydride.
• the invention further relates to compounds of the formula III", in which n represents a whole number from 0 to 10, W' represents hydrogen, alkyl having 1 to 18 C atoms or aralkyl having 7 to 10 C atoms and R 3 , R 4 and/or R 5 ##STR9## represent hydrogen, or R 3 and R 4 or R 4 and R 5 together each denote a chemical bond.
• Preferred compounds of the formula III" are compounds of the formula III' ##STR10## wherein C-2, C-3a and C-(6+n)a have the same configuration as in formula III, n denotes 0, 1 or 2 and W' has the meaning of W in formula III and also denotes hydrogen. According to the invention, these compounds serve as starting materials for the synthesis of compounds of the formula I and can be prepared according to the invention by the following procedures.
• One synthetic variant starts with a compound of the formula IX ##STR11## wherein the H atoms on the C atoms 3a and (6+n)a have the cis or trans configuration relative to one another and wherein n denotes the number 0, 1 or 2.
• These compounds of the formula IX are acylated in a known manner, an aliphatic or aromatic acyl radical, preferably an acetyl or benzoyl radical, being bonded to the nitrogen atom, and the N-acylated compounds obtained are anodically oxidized (in analogy with Liebigs Ann. Chem. 1978 page 1719) in an aliphatic alcohol, preferably an alkanol having 1 to 4 C atoms, in particular methanol, in the presence of a conducting salt, preferably at temperatures in the range from 0° to +40° C. with formation of a compound of the formula X, wherein n denotes 0, 1 or 2 and ##STR12## R 3 denotes (C 1 -C 4 )-alkyl.
• the compound of the general formula X obtained is reacted with trimethylsilyl cyanide in accordance with Tetrahedron Letters 1981 page 141 in an aprotic organic solvent, such as, for example, in a hydrocarbon, halogenated hydrocarbon, in ether or in THF at temperatures in the range from -60° C. to +20° C., preferably -40° C. to ⁇ 0° C.
• an aprotic organic solvent such as, for example, in a hydrocarbon, halogenated hydrocarbon, in ether or in THF at temperatures in the range from -60° C. to +20° C., preferably -40° C. to ⁇ 0° C.
• HCl or HBr is used as the acid.
• the esterified if appropriate in the acid hydrolysis of the nitrile group.
• halogenating agents are halides of inorganic acid, such as PCl 5 , SO 2 Cl 2 , POCl 3 , SOCl 2 , PBr 3 or halogens, such as bromine. It is advantageous to use PCl 5 or POCl 3 combined with SO 2 Cl 2 .
• the intermediate initially formed is an imide halide, which, with the halogenating agent mentioned and subsequent hydrolysis under basic conditions, preferably with aqueous alkali metal carbonate, reacts further to give a compound of the formula XIV.
• the compounds of the formula XIV are subsequently reduced catalytically in a polar protic solvent, such as, for example, an alcohol, preferably ethanol, or a carboxylic acid, such as, for example, acetic acid, with the addition of an acid acceptor, such as, for example, sodium acetate or triethylamine, to give a compound of the formula XV ##STR17## wherein n and Hal have the abovementioned meanings.
• suitable catalysts are Raney nickel or platinum on animal charcoal.
• Compounds of the formula XV can also be prepared directly by halogenation of the compounds of the formula XIII by using smaller amounts of the abovementioned halogenating agent.
• the compounds of the formula III' wherein the H atoms on the C atoms 3a and (6+n)a have the cis configuration, can be prepared from the compound of the formula XVI, wherein n denotes 0, 1 or 2, ##STR18## by reducing the latter by means of platinum oxide/acetic acid in accordance with Ann. Chim. 62, 200 (1972) to give a compound of the abovementioned formula XIII and reacting the latter in accordance with the procedures described above.
• Compounds of the formula XVI are known from J. Org. Chem. 29, 2780 (1964).
• Trans-configurated 2-azabicycloalkane-3-carboxylic acids of the formula III' in which n denotes a whole number from 0 to 10 and W' represents hydrogen, and their alkyl and aralkyl esters can be prepared from enamines of the formula XVII in which n has the previous meaning and X 1 represents dialkylamino having 2 to 10 C atoms or a radical of the formula XVIIa, wherein m and o denote a whole number from 1 to 3, (m+o) ⁇ 3 and A denotes CH 2 , NH, O or S (Organikum, 6th edition, page 370, 1967), ##STR19## together with N-acylated ⁇ -halogeno- ⁇ -aminopropionates of the formula XVIII (for the free amino compound, cf.
• X 2 represents halogen, preferably chlorine or bromine
• Y 1 represents alkanoyl having 1 to 5 C atoms, aroyl having 7 to 9 C atoms or other protective groups which are customary in peptide chemistry and which can be split off by acid
• R 4 ' represents alkyl having 1 to 5 C atoms or aralkyl having 7 to 9 C atoms, ##STR20## or together with acrylates of the formula XIX (Chem. Ber.
• Particularly suitable groups Y 1 in the ⁇ -bromo- or chloro- ⁇ -aminocarboxylates of the formula XVIII are formyl, acetyl, propionyl or benzoyl, or other protective groups which can be split off with acid, such as, for example, tert.-butyloxycarbonyl.
• the C 1 -C 3 -alkyl or the benzyl esters are preferably employed.
• the acrylic acid derivatives of the formula XIX which are produced as intermediates from the ⁇ -halogeno- ⁇ -aminopropionates under the basic conditions of the experiment, are also suitable as the starting compounds. They are prepared, for example, by treatment of the halogenoaminopropionic acid derivatives or the analogous o-tosylserine derivatives with bases. Tertiary organic bases, such as, for example, triethylamin are preferably used. It is advantageous to carry out the reaction with the addition of small amounts of polymerization inhibitors, such as, for example, hydroquinone in organic solvents.
• the acrylic acid derivatives of the formula XIX can be employed instead of the halogenopropionic acid derivatives under identical reactions conditions.
• Suitable solvents for the enamine synthesis are organic solvents which cannot be alkylated, such as, for example, dimethylacetamide, DMSO, THF or toluene. Dimethylformamide is particularly suitable.
• the hydrolysis of the N-acyl group necessary for cyclization is generally brought about at the same time as cleavage of the ester function by strong aqueous mineral acids, such as sulfuric acid or, preferably, hydrochloric acid.
• strong aqueous mineral acids such as sulfuric acid or, preferably, hydrochloric acid.
• the latter can be converted by hydrogenation in the presence of metal catalysts or reaction with borane-amine complexes or complex borohydrides into the trans-configurated 2-azabicyclocarboxylates of the formula III'.
• Noble metal or nickel catalysts are suitable for catalytic hydrogenation.
• the isomeric ratio occurring on catalytic hydrogenation depends on the reaction conditions and the type of catalyst used.
• Suitable solvents for the catalytic hydrogenation are ethanol, methanol, ethyl acetate, dioxane, glacial acetic acid or mixtures of these solvents.
• Isolation of the pure trans compounds of the formula III'b can, for example, be carried out by chromatographic processes or crystallization processes.
• the pure trans compound of the formula III'b is advantageously separated out of the mixture of diastereomers from the amine-borane-complex or boronate reduction by fractional crystallization.
• the compounds of the formula III' can, if appropriate, be converted into the C 1 -C 18 -alkyl or C 7 -C 10 -aralkyl esters by methods which are described, for example, in Houben-Weyl, volume VIII (1952).
• the compounds of the formula II with Y and Z being hydrogen, R 1 being methyl and R 2 being methyl or ethyl and X being phenyl which are used as starting materials for the preparation of the compounds of the formula I are known (European Patent Application No. 37,231).
• the compounds of the formula II can be prepared by various procedures.
• One sythetic variant starts from a ketone of the abovementioned formula VII, which is reacted by known procedures in a Mannich reaction with a compound of the abovementioned formula VI together with aminoacid esters of the formula XXII ##STR25## wherein R 1 and W have the abovementioned meanings, to give a compound of the formula XXIII, wherein R 1 , R 2 , X and W have the abovementioned meanings, with the proviso that in the case where W denotes a radical which can be split off by hydrogenolysis, in particular benzyl, R 2 may not have the meaning of W.
• radical W is split off by hydrogenolysis using, for example, palladium, compounds of the formula II with Y and Z being hydrogen are obtained. If the radical W is split off with acids, such as, for example, trifluoroacetic acid or hydrochloric acid in an inert organic solvent, such as, for example, dioxane, compounds of the formula II with Y and Z together being oxygen are obtained.
• acids such as, for example, trifluoroacetic acid or hydrochloric acid in an inert organic solvent, such as, for example, dioxane
• the compounds of the formula XXIII are obtained as mixtures of diastereomers.
• Preferred diastereomers of the formula XXIII are those in which the chiral C atoms labeled with an asterisk are each in the S configuration. These can be separated out by recrystallization or by chromatography, for example on silica gel. The configurations of the chiral C atoms are maintained during the subsequent splitting off of the radical W.
• the compounds of the abovementioned formula IV used as starting materials for the preparation of the compounds of the formula I are obtained by known procedures from compounds of the abovementioned formula III by reaction with an N-protected 2-aminocarboxylic acid of the formula XXIV ##STR26## wherein V is a protective group and R 1 has the abovementioned meaning.
• suitable protective groups V which are split off again after completion of the reaction, are the groups benzyloxycarbonyl or tert.-butoxycarbonyl.
• reaction of a compound of the formula II with a compound of the formula III to prepare a compound of the formula I is carried out by a condensation reaction known in peptide chemistry, the condensing agent added being, for example, dicyclohexylcarbodiimide and 1-hydroxybenzotriazole.
• the catalyst used is preferably palladium, while the acids employed for the acid removal of the radical W are preferably trifluoroacetic acid or hydrogen chloride.
• the compounds of the formula III' obtained according to the procedures described above are produced as racemic mixtures and can be employed as such in the further syntheses described above. However, they can also be employed as the pure enantiomers after separation of the racemates into the optical antipodes by customary methods, for example, via salt formation with optically active bases or acids.
• the compounds of the formula I are produced as racemates, these can also be resolved into their enantiomers by customary methods, such as, for example, via salt formation with optically active bases or acids.
• the compounds of the formula I according to the invention are in the form of internal salts. Since they are amphoteric compounds, they can form salts with acids or bases. These salts are prepared in a customary manner by reaction with one equivalent of acid or base.
• the compounds of the formula I and their salts have long-lasting and powerful hypotensive activities. They are strong inhibitors of the angiotensin converting enzyme (ACE inhibitors). They can be employed to control high blood pressure of various etiologies. It is also possible to combine them with other compounds having hypotensive, vasodilator or diuretic activity. Typical representatives of these classes of active compounds are described, for example, in Erhardt-Ruschig, Arzneiffen (Drugs), 2nd edition, Weinheim, 1972. They can be used intravenously, subcutaneously or perorally.
• ACE inhibitors angiotensin converting enzyme
• the dosage on oral administration is 1-100 mg, preferably 1-40 mg, for a single dose for an adult patient of normal weight. This can also be increased in severe cases, since no toxic properties have been observed hitherto. A decrease in the dose is also possible and is particularly appropriate when diuretics are administered concurrently.
• the compounds according to the invention can be administered orally or parenterally in an appropriate pharmaceutical formulation.
• the active compounds are mixed with the additives customary for this purpose, such as vehicles, stabilizers or inert diluents and converted by customary methods into suitable forms for administration, such as tablets, coated tablets, hard capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions.
• Inert vehicles which can be used are, for example, gum arabic, magnesium carbonate, potassium phosphate, lactose, glucose or starch, particularly corn starch.
• the formulation can either be as dry or as moist granules.
• suitable oily vehicles or solvents are plant and animal oils, such as sunflower oil or cod-liver oil.
• the active compounds or their physiologically tolerated salts are converted into solutions, suspensions or emulsions, if desired together with the substances customary for this purpose such as solubilizers, emulsifiers or other auxiliaries.
• suitable solvents for the new active compounds and the corresponding physiologically tolerated salts are: water, physiological saline or alcohols, for example ethanol, propanediol or glycerol, additionally also sugar solutions, such as glucose or mannitol solutions, or also a mixture of the various solvents mentioned.
• the residue was taken up in 250 ml of pyridine, 93 ml of acetic anhydride were added and the mixture was allowed to react at 20° to 25° C. for 12 hours. After distilling off the pyridine, water was added to the residue and the mixture was made alkaline with concentrated aqueous sodium hydroxide. The aqueous phase was extracted with methylene chloride, the organic phase obtained was washed with 2N hydrochloric acid and with water. After drying and concentrating the solution, the residue was distilled.
• aqueous solution of the product was adjusted to a pH of 6.0 with a weakly basic ion exchanger. After filtration, the solution was evaporated and the residue was filtered through silica gel with a mixture of methylene chloride, methanol, glacial acetic acid and water in the ratio 20:10:0.5:0.5. The eluate was concentrated and the residue was triturated with diisopropyl ether.
• the distillate was heated with 10 ml of 10% strength acetic acid at 200° C. for 2 days. After cooling down, further product was obtained which was crystallized from methanol/water.
• the precipitate was filtered off with suction and the filtrate was adjusted to a pH of 6.5 with 1N sodium hydroxide and evaporated to dryness. The residue was extracted with boiling ethanol, concentrated and induced to crystallize.
• the mixture was stirred at 0° C. for 1 hour, then slowly warmed to room temperature and stirred at 20° to 25° C. overnight.
• This compound was prepared from diastereomer A 14 in Example 14 in analogy to the method A described in Example 17.
• the compounds of Examples 18 and 19 can also be prepared from the diastereomers A 15 and A 16 respectively by the method B described in Example 17.
• This compound was prepared from the compound in Example 18 in analogy to the process described in Example 20.
• This compound was prepared from the compound in Example 19 in analogy to the process described in Example 20.
• reaction solution was diluted with 25 ml of ethyl acetate and precipitated urea was filtered off with suction. After concentration in vacuo, the residue obtained was taken up in ether, the ethereal solution was washed with saturated aqueous sodium bicarbonate and with water, dried and evaporated. 3 g of the title compound were obtained as a mixture of diastereomers.
• the mixture of diastereomers can be separated over silica gel into the optically pure compounds using cyclohexane/ethyl acetate as the eluant.
• Examples 24 to 28 may be prepared in a procedure analogous to Example 23 using the appropriate bicyclic carboxylic acid ester compounds.
• the carboxylic acids described in the foregoing Examples 29 to 31 can also be prepared from the corresponding benzyl esters by catalytic hydrogenolysis (10% palladium on charcoal, ethanol, 20° to 25° C.).
• This compound was prepared according to the procedure described in Example 33 from the compound described in Example 29.
• This compound was prepared according to the procedure described in Example 33 from the compound described in Example 31.
• the organic phase was extracted 3 times in each case with aqueous potassium bisulfate, potassium bicarbonate and sodium chloride, dried and concentrated.
• the residue was chromatographed on silica gel with ethyl acetate/cyclohexane (1:3). The first fraction contained the desired product.
• reaction mixture was diluted with 20 ml of ethyl acetate and the precipitated dicyclohexylurea was filtered off. After concentration in vacuo, the residue was taken up in ether, washed twice with saturated aquous sodium bicarbonate, dried over sodium sulfate and evaporated. After chromatography on silica gel using ethyl acetate-cyclohexane as the eluant, 2 pale yellow oils were obtained in the ratio 1:1, and these each contain one isomer of the desired compound.
• the hydrochloride of the abovementioned compound was obtained as a colorless amorphous powder.
• Example 42c This compound was obtained from the mixture of products from Example 51, which were further reacted according to the procedure of Example 42.
• the isomers were separated by column chromatography on silica gel before hydrogenation in accordance with Example 42c.
• the hydrochloride was obtained as a colorless amorphous powder.
• the hydrochloride was obtained as a colorless amorphous powder.
• the hydrochloride was obtained as a colorless amorphous powder.
• the solution was concentrated under high vacuum, the residue obtained was taken up in 600 ml of water and the pH was adjusted to 2.0 with concentrated hydrochloric acid.
• the aqueous solution was extracted with ethyl acetate and the organic phase was dried over sodium sulfate and evaporated. The product was obtained as a yellow oil.
• This compound was prepared in analogy to the procedures (b) to (d) of Example 48 starting from pyrrolidinocycloheptene.
• This compound was prepared in analogy to the procedures (b) to (d) of Example 48, starting from pyrrolidinocyclopentene.
• a mixture of 1 mole of cyclopentanone, 1 mole of acrylonitrile, 0.05 mole of ammonium acetate and 3 ml of 30% strength ammonia were heated in a pressure vessel for 3 hours at 220° C.
• the mixture was filtered through silica gel with ethyl acetate/cyclohexane (1:1 and the residue obtained after evaporation of the filtrate was recrystallized from cyclohexane.
• the product melted at 118° to 120° C.
• This compound was prepared in analogy to the procedure described in Example 51 under (a), starting from cycloheptanone.
• This compound was prepared from 2 ⁇ ,3a ⁇ ,7a ⁇ -octahydroindole-2-carboxylic acid in analogy to the procedure described in Example 8.
• This compound was prepared from Z-alanine in analogy to the procedure described in Example 36 under (a), and separated from its isomer as described there.
• This compound was prepared in analogy to the procedure described in Example 39 under (a), starting from tert.-butyl N-(S-alanyl)-2S,3aR,7aS-octahydroindole-2-carboxylate.
• the tert.-butyl group was split off with trifluoroacetic acid.
• This compound was prepared in analogy to the procedure described in Example 40, starting from tert.-butyl N-(S-alanyl)-2S,3aR,7aS-octahydroindole-2-carboxylate.
• the tert.-butyl group was split off with trifluoroacetic acid.
• This compound was prepared in analogy to the procedure described in Example 40, starting from tert.-butyl N-(S-alanyl)-2S,3aS,7aR-octahydroindole-2-carboxylate.
• the tert.-butyl group was split off with trifluoroacetic acid.
• This compound was prepared in analogy to the procedure described in Example 40, starting from tert.-butyl N-(S-alanyl)-2S,3aR,6aS-octahydrocyclopenta[b]pyrrole-2-carboxylate.
• the tert.-butyl group was split off with trifluoroacetic acid.
• This compound was prepared in analogy to the procedure described in Example 41, followed by splitting off the tert.-butyl group with trifluoroacetic acid.
• This compound was prepared in analogy to the reaction procedure described in Example 41, following by splitting off the tertiary butyl group with trifluoroacetic acid.
• This compound was prepared in analogy to the procedure described in Example 41, followed by cleaving off the tert.-butyl group with trifluoroacetic acid.
• Example 2 290 g of the acetylamino derivative obtained in accordance with Example 1 were heated with 2N hydrochloric acid as indicated in Example 2. The mixture was evaporated in vacuo, the residue was taken up in 1 l of isopropanol and reduced with about 35 g of NaBH 4 which was added in portions in the course of 30 minutes. The reaction temperature was kept at 40°-50° C. The reaction was allowed to continue for about 4 hours, then the mixture was evaporated in vacuo, the pH was adjusted to 6.5 with dilute hydrochloric acid, solid sodium chloride was used to saturate, and the aminoacids were extracted several times with n-butanol. The residue remaining after concentration of the organic phase was fractionally crystallized from chloroform/diisopropyl ether as described in Example 2.
• Example 90 a 40 g of the compound obtained according to Example 90 a are hydrogenated in 800 ml of glacial acetic acid and 4 g of Pd/C (10%) at 100 bar and room temperature. After chromatography on silica gel with ethyl acetate/cyclohexane (1:3) as eluent and drying of the evaporation residue, 25 g of compound of the heading, m.p. 205°-213° C., nearly completely homogeneous according to thin-layer chromatography.
• Example 42b 1.5 g of the benzyl ester described in Example 42 a are reacted with 2.5 g of N-(1-R,S-carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosine, 1.3 g of dicyclohexylcarbodiimide and 0.8 g of 1-hydroxybenzotriazole. Chromatography of the crude product on silica gel with cyclohexane/ethyl acetate (1:1) as eluent gives 1 g of the compound of the heading in the form of a colorless oil. The 1 H-NMR data and the mass spectrum correspond to the indicated structure.
• the benzyl ester is hydrogenated according to the operation mode described in Example 42 a. 0.6 g of the compound of the heading is obtained as colorless, amorphous powder.
• Example 91 Prepared according to the operation mode of Example 91 with the use of the amino acid described in Example 52.
• the 1 H-NMR-data correspond to the indicated structure.

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